Heteroaromatic bicyclic derivatives useful as anticancer agents

ABSTRACT

The invention relates to compounds of the formula 1                    
     and to pharmaceutically acceptable salts and solvates thereof, wherein A, X, R 1 , R 3  and R 4  are as defined herein. The invention also relates to methods of treating abnormal cell growth in mammals by administering the compounds of formula 1 and to pharmaceutical compositions for treating such disorders which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.

This application claims the benefit of U.S. Provisional Application No.60/117,341 filed Jan. 27, 1999, which is incorporated herein byreference.

BACKGROUND OF THE INVENTION

This invention relates to novel bicyclic derivatives that are useful inthe treatment of abnormal cell growth, such as cancer, in mammals. Thisinvention also relates to a method of using such compounds in thetreatment of abnormal cell growth in mammals, especially humans, and topharmaceutical compositions containing such compounds.

It is known that a cell may become cancerous by virtue of thetransformation of a portion of its DNA into an oncogene (i.e., a genewhich, on activation, leads to the formation of malignant tumor cells).Many oncogenes encode proteins that are aberrant tyrosine kinasescapable of causing cell transformation. Alternatively, theoverexpression of a normal proto-oncogenic tyrosine kinase may alsoresult in proliferative disorders, sometimes resulting in a malignantphenotype.

Receptor tyrosine kinases are enzymes which span the cell membrane andpossess an extracellular binding domain for growth factors such asepidermal growth factor, a transmembrane domain, and an intracellularportion which functions as a kinase to phosphorylate specific tyrosineresidues in proteins and hence to influence cell proliferation. Otherreceptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr,VEGF and TGF-β. It is known that such kinases are frequently aberrantlyexpressed in common human cancers such as breast cancer,gastrointestinal cancer such as colon, rectal or stomach cancer,leukemia, and ovarian, bronchial or pancreatic cancer. It has also beenshown that epidermal growth factor receptor (EGFR), which possessestyrosine kinase activity, is mutated and/or overexpressed in many humancancers such as brain, lung, squamous cell, bladder, gastric, breast,head and neck, oesophageal, gynecological and thyroid tumors.

Accordingly, it has been recognized that inhibitors of receptor tyrosinekinases are useful as selective inhibitors of the growth of mammaliancancer cells. For example, erbstatin, a tyrosine kinase inhibitor,selectively attenuates the growth in athymic nude mice of a transplantedhuman mammary carcinoma which expresses epidermal growth factor receptortyrosine kinase (EGFR) but is without effect on the growth of anothercarcinoma which does not express the EGF receptor. Thus, the compoundsof the present invention, which are selective inhibitors of certainreceptor tyrosine kinases, are useful in the treatment of abnormal cellgrowth, in particular cancer, in mammals.

Various other compounds, such as styrene derivatives, have also beenshown to possess tyrosine kinase inhibitory properties. More recently,five European patent publications, namely EP 0 566 226 A1 (publishedOct. 20, 1993), EP 0 602 851 A1 (published Jun. 22, 1994), EP 0 635 507A1 (published Jan. 25, 1995), EP 0 635 498 A1 (published Jan. 25, 1995),and EP 0 520 722 A1 (published Dec. 30, 1992), refer to certain bicyclicderivatives, in particular quinazoline derivatives, as possessinganti-cancer properties that result from their tyrosine kinase inhibitoryproperties. Also, World Patent Application WO 92/20642 (published Nov.26, 1992), refers to certain bis-mono and bicyclic aryl and heteroarylcompounds as tyrosine kinase inhibitors that are useful in inhibitingabnormal cell proliferation. World Patent Applications WO96/16960(published Jun. 6, 1996), WO 96/09294 (published Mar. 6, 1996), WO97130034 (published Aug. 21, 1997), WO 98/02434 (published Jan. 22,1998), WO 98/02437 (published Jan. 22, 1998), and WO 98/02438 (publishedJan. 22, 1998), also refer to substituted bicyclic heteroaromaticderivatives as tyrosine kinase inhibitors that are useful for the samepurpose.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula 1

and to pharmaceutically acceptable salts and solvates thereof, wherein:X is N or CH;

A represents a fused 5, 6 or 7-membered ring optionally containing 1 to4 heteroatoms which may be the same or different and which are selectedfrom —N(R¹)—, O, and S(O)_(j), wherein j is an integer from 0 to 2, thefused ring containing a total of 1, 2 or 3 double bonds inclusive of thebond in the pyridine or pyrimidine ring to which it is fused wherein theR¹ group attached to the nitrogen is absent if a double bond includesthe foregoing optional nitrogen moiety —N(R¹)—, with the proviso thatthe fused ring does not form part of a purine and that the fused ringdoes not contain two adjacent O or S(O)_(j) atoms, and wherein thecarbon atoms of the A moiety are optionally substituted with 1 to 3 R⁵groups;

each R¹ and R² is independently H or C₁-C₆ alkyl;

R³ is —(CR¹R²)_(m)-R⁸ wherein m is 0 or 1;

or R¹ and R³ are taken together to form a group of the formula

wherein said group is optionally substituted with 1 to 3 R⁵ groups;

R⁴ is —(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5, wherein said R⁴groups are substituted with 1 to 3 groups independently selected from—(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl),—(CR¹R²)_(q)O(CR¹R²)_(r)R⁹, and —(CR¹R²)_(q)R⁹ wherein q and r are eachindependently an integer from 0 to 5, and wherein the heterocyclic, aryland alkyl moieties of the foregoing groups are optionally substitutedwith 1 to 3 R¹⁰ groups;

each R⁵ is independently selected from halo, hydroxy, —NR¹R², C₁-C₆alkyl, trifluoromethyl, C₁-C₆ alkoxy, and trifluoromethoxy;

each R⁶ and R⁷ is independently selected from H, C₁-C₆ alkyl,—(CR¹R²)_(t)(C₆-C₁₀ aryl), and —(CR¹R²)_(t)(4-10 membered heterocyclic),wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of theheterocyclic group are optionally substituted with an oxo (═O) moiety,and the alkyl, aryl and heterocyclic moieties of the foregoing R⁶ and R⁷groups are optionally substituted with 1 to 3 substituents independentlyselected from halo, cyano, nitro, —NR¹R², trifluoromethyl,trifluoromethoxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxy,and C₁-C₆ alkoxy;

each R⁸ is independently selected from —(CR¹R²)_(t)(C₆-C₁₀ aryl) and—(CR¹R²)_(t)(4-10 membered heterocyclic), wherein t is an integer from 0to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionallysubstituted with an oxo (═O) moiety, and each of the foregoing R⁸ groupsis optionally substituted with 1 to 5 R¹⁰ groups;

R⁹ is a fused or bridged bicyclic ring or a spirocyclic ring, whereinsaid ring contains from 5 to 12 carbon atoms in which up to 2 carbonatoms are optionally replaced with a hetero moiety selected from O,S(O)_(j) wherein j is an integer from 0 to 2, and —NR¹¹—, provided thattwo O atoms, two S(O)_(j) moieties, an O atom and a S(O)_(j) moiety, anN atom and an S atom, or an N atom and an O atom are not attacheddirectly to each other, and wherein said ring is saturated or partiallyunsaturated with up to two carbon-carbon double bonds, and the carbonatoms of said ring are optionally substituted with 1 to 4 R¹⁰ groups;

or where R⁹ is as —NR¹R⁹ then R⁹ optionally can be taken together withR¹ and the nitrogen to which R¹ and R⁹ are attached to form a fused orbridged bicyclic ring or a spirocyclic ring, wherein said ring issaturated and contains from 5 to 12 carbon atoms in which up to 2 carbonatoms are optionally replaced with a hetero moiety selected from O,S(O)_(j) wherein j is an integer from 0 to 2, and —NR¹—, provided thattwo O atoms, two S(O)_(j) moieties, or an O atom and a S(O)_(j) moietyare not attached directly to each other, and wherein the carbon atoms ofsaid rings are optionally substituted with 1 to 4 R¹⁰ groups;

each R¹⁰ is independently selected from halo, cyano, nitro,trifluoromethoxy, trifluoromethyl, azido, hydroxy, C₁-C₆ alkoxy, C₁-C₁₀alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)R⁵, —C(O)OR⁶, —OC(O)R⁶,—NR⁸C(O)R⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, —SO₂NR⁶R⁷, —S(O)_(j)(C₁-C₆alkyl) wherein j is an integer from 0 to 2, —(CR¹R²)_(t)(C₆-C₁₀ aryl),—(CR¹R²)_(t)(4-10 membered heterocyclic),—(CR¹R²)_(q)C(O)(CR¹R²)_(t)(C₆-C₁₀ aryl),—(CR¹R²)_(q)C(O)(CR¹R²)_(t)(4-10 membered heterocyclic),—(CR¹R²)_(t)O(CR¹R²)_(q)(C₆-C₁₀ aryl), —(CR¹R²)_(t)O(CR¹R²)_(q)(4-10membered heterocyclic), —(CR¹R²)_(q)SO₂(CR¹R²)_(t)(C₆-C₁₀ aryl), and—(CR¹R²)_(q)SO₂(CR¹R²)_(t)(4-10 membered heterocyclic), wherein q and tare each independently an integer from 0 to 5, 1 or 2 ring carbon atomsof the heterocyclic moieties of the foregoing R¹⁰ groups are optionallysubstituted with an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl,aryl and heterocyclic moieties of the foregoing R¹⁰ groups areoptionally substituted with 1 to 3 substituents independently selectedfrom halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR⁶,—C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R¹, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷,C₁-C₆ alkyl, C₂-C₆ alkenyl C₂-c₆ alkynyl —(CR¹R²)_(t)(C₆-C₁₀ aryl), and—(CR¹R²)_(t)(4-10 membered heterocyclic), wherein t is an integer from 0to 5;

R¹¹ is H, C₁-C₆ alkyl, —C(O)R⁶ or —SO₂R⁶;

and wherein any of the above-mentioned substituents comprising a CH₃(methyl), CH₂ (methylene), or CH (methine) group which is not attachedto a halogeno, SO or SO₂ group or to a N, O or S atom optionally bearson said group a substituent selected from hydroxy, halo, C₁-C₄ alkyl,C₁-C₄ alkoxy and —NR¹R².

In a specific embodiment of the present invention, the A moiety of thecompounds of formula 1 is selected from

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.

Other specific embodiments of the compounds of formula 1 include thosewherein A is elected from

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.

Other specific embodiments of the compounds of formula 1 include thosewherein A is selected from

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.

Other specific embodiments of the compounds of formula 1 include thosewherein A is selected from

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.

Other specific embodiments of the compounds of formula 1 include thosewherein A is

wherein the above A moieties bear an R⁴ group as a substituent andoptionally bear 1 to 3 R⁵ groups as substituents.

Other specific embodiments of the compounds of formula 1 include thosewherein R⁴ is —(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5, wherein said R⁴groups are substituted with 1 to 3 groups independently selected from—(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl),—(CR¹R²)_(q)O(CR¹R²)_(r)R⁹, and —(CR¹R²)_(q)R⁹ wherein q and r are eachindependently an integer from 0 to 3, and wherein the heterocyclic, aryland alkyl moieties of the foregoing groups are optionally substitutedwith 1 to 3 R¹⁰ groups.

Other specific embodiments of the compounds of formula 1 include thosewherein R³ is —(CR¹R²)_(m)R⁸ wherein m is 0 or 1 and R⁸ is selected from—(CR¹R²)_(t)(phenyl), —(CR¹R²)_(t)(pyridyl), —(CR¹R²)_(t)(pyrimidinyl),—(CR¹R²)_(t)(indolyl), —(CR¹R²)_(t)(indazolyl) and—(CR¹R²)_(t)(benzimidazolyl), wherein t is an integer from 0 to 5, andeach of the foregoing R⁸ groups is optionally substituted with 1 to 5R¹⁰ groups.

Other specific embodiments of the compounds of formula 1 include thoseselected from the group consisting of:

{[4-(6-[4-(6-Amino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]quinazolin-4-yl}-(4-phenoxy-phenyl)-amine;

(3-{4-[4-(4-Benzyl-phenylamino)quinazolin6-yl]-benzy}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

(3-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

(3-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

(6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine;

(6-{4-[(1-Aza-bicyclo[2.2.2]-3-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-benzyl-phenyl)-amine;

6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(1-benzenesulfonyl-1H-indol-5-yl)-amine;

6-{4-[(3-Aza-bicyclo[3.1.0]hex-6-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine;

3-{4-[4-(4-Benzyl-phenylamino)-quinazolin6-yl]-benzylamino}-8-methyl-8-aza-bicyclo[3.2.1]octan6-ol;

(4-Benzyl-phenyl)-{6-[4-(6-methoxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-amine

{6-[4-(6-Methoxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin4-yl}-(4-phenoxy-phenyl)-amine;

(3-{4-[4-(4-[1,2,3]Thiadiazol-5-yl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

(3-{4-[4-(4-Cyclohexyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex6-yl)-methanol;

(3-{4-[4-(4-p-Tolyloxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex6-yl)-methanol;

(3-{4-[4-(Biphenyl4-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

(3-{4-[4-(4-Ethyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

4-{6-[4-(6-Hydroxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-ylamino}-N-phenyl-benzamide;

[3-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol;

(3-{4-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

(1-Benzenesulfonyl-1H-indol-5-yl)-(6-{4-[(3-oxa-bicyclo[3.1.0]hex-6-ylamino)-methyl}-phenyl)-quinazolin-4-yl)-amine;

8-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;

8-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-yl}-benzyl)-8-aza-bicyclo[3.2.1]octan-3-ol;

8-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;

8-{4-[4-(1-Benzyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;

(3-{4-[4-(6-Phenoxy-pyridin-3-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

(3-{5-[4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-pyrdin-2-ylmethyl}3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

{3-[4-(4-Phenoxy-phenylamino)-quinazolin-6ylmethyl]-3-aza-bicyclo[3.1.0]hex6-yl}methanol;

5-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)-methanol;

(5-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)-methanol;

(6-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-6-aza-spiro(2.5]oct-1-yl)-methanol;

(6-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-6-azaspiro[2.5]oct-1-yl)-methanol;

(5-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.4]hept-1-yl)-methanol;

(5-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.4]hept-1-yl)-methanol;

(5-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)-methanol;

and the pharmaceutically acceptable salts and solvates of the foregoingcompounds.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt or solvate thereof, that iseffective in treating abnormal cell growth. In one embodiment of thismethod, the abnormal cell growth is cancer, including, but not limitedto, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, uterine cancer,ovarian cancer, rectal cancer, cancer of the anal region, stomachcancer, colon cancer, breast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer ofthe urethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said method, said abnormal cell growth is a benignproliferative disease, including, but not limited to, psoriasis, benignprostatic hypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal anamount of a compound of formula 1, or a pharmaceutically acceptable saltor solvate thereof, that is effective in treating abnormal cell growthin combination with an anti-tumor agent selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

This invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt or solvate thereof, that iseffective in treating abnormal cell growth, and a pharmaceuticallyacceptable carrier. In one embodiment of said composition, said abnormalcell growth is cancer, including, but not limited to, lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said pharmaceutical composition, said abnormal cell growthis a benign proliferative disease, including, but not limited to,psoriasis, benign prostatic hypertrophy or restinosis.

The invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human, whichcomprises an amount of a compound of formula 1, as defined above, or apharmaceutically acceptable salt or solvate thereof, that is effectivein treating abnormal cell growth in combination with a pharmaceuticallyacceptable carrier and an anti-tumor agent selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, and anti-androgens.

The invention also relates to a method of preparing a compound of theformula 1

and to pharmaceutically acceptable salts and solvates thereof, whereinA, X, R¹, R⁴ and R³ are as defined above, which comprises either (a)reacting a compound of the formula 5 with a compound of the formula 6

wherein Z is a leaving group and A, X, R¹, R³, and R⁴ are as definedabove, or (b) reacting a compound of the formula 2 with a compound ofthe formula 6

wherein X, A, R¹, and R³ are as defined above and Z¹ is an activatinggroup to provide an intermediate of the formula 7

wherein Z¹, X, A, R¹, and R³ are as defined above, and treating thecompound of formula 7with a coupling partner of the formulaX¹—(CR¹R²)_(t)(C₆-C₁₀ aryl) or X¹—(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t, R¹ and R² are as defined above as provided inthe definition of R⁴, the aryl and heterocyclic groups of the foregoinggroups are substituted with a group that includes an aldehyde or acidmoiety, and X¹ is —B(OH)₂ or —Sn(C₁-C₅ alkyl)₃, to provide a compound offormula 8

wherein X, A, R¹, and R³ are as defined above, and Z² is—(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10 membered heterocyclic),wherein t, R¹ and R² are as defined above as provided in the definitionof R⁴, and the aryl and heterocyclic groups of the foregoing Z² groupsare substituted with a group that includes an aldehyde or acid moiety,and modifying said acid or aldehyde moiety to introduce a group selectedfrom —(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl),—(CR¹R²)_(q)OR⁹, and —(CR¹R²)_(q)R⁹, wherein R¹, R², R⁹ and q are asdefined above.

“Abnormal cell growth”, as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes theabnormal growth of: (1) tumor cells (tumors) that proliferate byexpressing a mutated tyrosine kinase or overexpression of a receptortyrosine kinase; (2) benign and malignant cells of other proliferativediseases in which aberrant tyrosine kinase activation occurs; and (4)any tumors that proliferate by receptor tyrosine kinases.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

The term “halo”, as used herein, unless otherwise indicated, meansfluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloroand bromo.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched, orcyclic moieties (including fused and bridged bicyclic and spirocyclicmoieties), or a combination of the foregoing moieties. For an alkylgroup to have cyclic moieties, the group must have at least three carbonatoms.

The term “alkenyl”, as used herein, unless otherwise indicated, includesalkyl moieties having at least one carbon-carbon double bond whereinalkyl is as defined above and including E and Z isomers of said alkenylmoiety.

The term “alkynyl”, as used herein, unless otherwise indicated, includesalkyl moieties having at least one carbon-carbon triple bond whereinalkyl is as defined above.

The term “alkoxy”, as used herein, unless otherwise indicated, includesO-alkyl groups wherein alkyl is as defined above.

The term “aryl”, as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl.

The term “4-10 membered heterocyclic”, as used herein, unless otherwiseindicated, includes aromatic and non-aromatic heterocyclic groupscontaining one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4-10 atoms in its ring system,and with the proviso that the ring of said group does not contain twoadjacent O or S atoms. Non-aromatic heterocyclic groups include groupshaving only 4 atoms in their ring system, but aromatic heterocyclicgroups must have at least 5 atoms in their ring system. The heterocyclicgroups include benzo-fused ring systems. An example of a 4 memberedheterocyclic group is azetidinyl (derived from azetidine). An example ofa 5 membered heterocyclic group is thiazolyl and an example of a 10membered heterocyclic group is quinolinyl. Examples of non-aromaticheterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listedabove, may be C-attached or N-attached where such is possible. Forinstance, a group derived from pyrrole may be pyrrol-1-yl (N-attached)or pyrrol-3-yl (C-attached). Further, a group derived from imidazole maybe imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). An exampleof a heterocyclic group wherein 2 ring carbon atoms are substituted withoxo (═O) moieties is 1,1-dioxo-thiomorpholinyl.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups which maybe present in the compounds of formula 1. The compounds of formula 1that are basic in nature are capable of forming a wide variety of saltswith various inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds of formula 1 are those that form non-toxic acid additionsalts, i.e., salts containing pharmacologically acceptable anions, suchas the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate,estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate,laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate,napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate,pantothenate, phospate/diphosphate, polygalacturonate, salicylate,stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodode, and valerate salts.

In the compounds of formula 1, where terms such as (CR¹R²)_(q) or(CR¹R²)_(t) are used, R¹ and R² may vary with each iteration of q or tabove 1. For instance, where q or t is 2 the terms (CR¹R²)_(q) or(CR¹R²)_(t) may equal —CH₂CH₂—, or —CH(CH₃)C(CH₂CH₃)(CH₂CH₂CH₃)—, or anynumber of similar moieties falling within the scope of the definitionsof R¹ and R². Further, as noted above, any substituents comprising a CH₃(methyl), CH₂ (methylene), or CH (methine) group which is not attachedto a halogeno, SO or SO₂ group or to a N, O or S atom optionally bearson said group a substituent selected from hydroxy, C₁-C₄ alkoxy and—NR¹R².

Certain compounds of formula 1 may have asymmetric centers and thereforeexist in different enantiomeric forms. All optical isomers andstereoisomers of the compounds of formula 1, and mixtures thereof, areconsidered to be within the scope of the invention. With respect to thecompounds of formula 1, the invention includes the use of a racemate,one or more enantiomeric forms, one or more diastereomeric forms, ormixtures thereof. The compounds of formula 1 may also exist astautomers. This invention relates to the use of all such tautomers andmixtures thereof.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in Formula 1, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labelled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of Formula 1 of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

DETAILED DESCRIPTION OF THE INVENTION

General synthetic methods which may be referred to for preparing thecompounds of the present invention are provided in U.S. Pat. No.5,747,498 (issued May 5, 1998), U.S. patent application Ser. No.08/953078 (filed Oct. 17, 1997), WO 98/02434 (published Jan. 22, 1998),WO 98/02438 (published Jan. 22, 1998), WO 96/40142 (published Dec. 19,1996), WO 96/09294 (published Mar. 6, 1996), WO 97/03069 (published Jan.30, 1997), WO 95/19774 (published Jul. 27, 1995) and WO 97/13771(published Apr. 17, 1997). The foregoing patents and patent applicationsare incorporated herein by reference in their entirety. Certain startingmaterials may be prepared according to methods familiar to those skilledin the art and certain synthetic modifications may be done according tomethods familiar to those skilled in the art. A standard procedure forpreparing 6-iodoquinazolinone is provided in Stevenson, T. M.,Kazmierczak, F., Leonard, N. J., J. Org. Chem. 1986, 51, 5, p. 616.Palladium-catalyzed boronic acid couplings are described in Miyaura, N.,Yanagi, T., Suzuki, A. Syn. Comm. 1981, 11, 7, p. 513. Reduction ofaromatic nitro groups can be performed by methods outlined in Brown, R.K., Nelson, N. A. J. Org. Chem. 1954, p. 5149; Yuste, R., Saldana, M,Walls, F., Tet. Lett. 1982, 23, 2, p. 147; or in WO/9609294, referred toabove. Nitro substituted N1-phenylsulfonylindoles/indazoles can beprepared by the methods found in Sundberg, R. J., Bloom, J. D., J. Org.Chem. 1980, 45, 17, p. 3382; Ottoni, O. et al. Tetrahedron, 1998, 54,13915; or Boger, Dale L. et. al.; J. Org. Chem; 55; 4; 1990; 1379.Substituted nitro N1-benzylindoles/indazoles can be prepared by methodsfound in Makosza, M.; Owczarczyk, Z.; J. Org. Chem., 54, 21, 1989, 5094;Adebayo, Adelaide T. O. M., Bowman, W. Russell, Salt, W. G., J. Chem.Soc. Perkin Trans.1, 1989, 1415; or WO 98/02434, referred to above.Benzyloxy-nitrobenzene intermediates may be prepared by methods found inWO 98/02434, referred to above.

Alternatively, arylmethoxy, or aryloxy nitrobenzene derivatives may beprepared from halo nitrobenzene precursors by nucleophilic displacementof the halide with an appropriate alcohol as described in Dinsmore, C.J. et al., Bioorg. Med. Chem. Lett., 7, 10, 1997, 1345; or Loupy, A. etal., Synth. Commun., 20, 18, 1990, 2855; or Brunelle, D. J. Tet. Lett.,25, 32, 1984, 3383. Fused and bridged bicyclic amines were synthesizedaccording to the methods described in: Brighty, K. E. and Castaldi, M.J., Synlett, 1996, 1097; and Momose, T. et al., J. Chem. Soc. PerkinTrans. 1, 1997, 1307. Spirocyclic amines were synthesized according tomethods found in WO 92122550. Starting materials, the synthesis of whichis not specifically described herein or the published referencesreferred to above, are either commercially available or can be preparedusing methods well known to those of skill in the art.

In each of the reactions discussed or illustrated in the Schemes above,pressure is not critical unless otherwise indicated. Pressures fromabout 0.5 atmospheres to about 5 atmospheres are generally acceptable,and ambient pressure, i.e., about 1 atmosphere, is preferred as a matterof convenience.

Where the compound of formula 6, HNR¹R³, is an optionally substitutedindole or indoline moiety, such compounds may be prepared according toone or more methods known to those skilled in the art. Such methods aredescribed in PCT international patent application publication number WO95/23141 and in W. C. Sumpter and F. M. Miller, “Heterocyclic Compoundswith Indole and Carbazole Systems,” in volume 8 of “The Chemistry ofHeterocyclic Compounds”, Interscience Publishers Inc., New York (1954).Optional substituents may be included as appropriate before or after thecoupling step illustrated in Scheme 1. Prior to the coupling step,primary and secondary amino moieties (other than said amine of formula6, HNR¹R³) are preferably protected using a nitrogen protecting groupknown to those skilled in the art. Such protecting groups and their useare described in T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis,” Second Edition, John Wiley & Sons, New York, 1991.

With reference to Scheme 1 above, the compound of formula 1 may beprepared by coupling the compound of formula 5, wherein X, A, and R⁴ areas defined above and Z is a leaving group, such as a phenoxy or aphenoxy derivative substituted with halo, cyano, nitro, or lower alkyl,with an amine of the formula 6, HNR¹R³, wherein R¹ and R³ are as definedabove, in an anhydrous solvent, in particular a solvent selected fromDMF (N,N-dimethylformamide), DME (ethylene glycol dimethyl ether), DCE(dichloroethane), t-butanol, and phenol, or a mixture of the foregoingsolvents, a temperature within the range of about 50-150° C. for aperiod ranging from 1 to 48 hours. The compound of formula 6, HNR¹R³,may be prepared by methods known to those skilled in the art, such asreduction of nitriles, reduction of imines or enamines, reduction ofoximes, primary and secondary amides, reduction of a nitro group orreductive amination of either R¹NH₂ and R³CH(O) or R³NH₂ and R¹CH(O).The compound of formula 5 may be prepared by treating a compound offormula 4, wherein Z² is —(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10membered heterocyclic), wherein t, R¹ and R² are as defined above asprovided in the definition of R⁴, and the aryl and heterocyclic groupsof the foregoing groups are substituted by a group that includes analdehyde or acid moiety that may be modified to introduce one or moregroups selected from —(CR¹R²)_(q)NR¹R⁹, —CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl),—(CR¹R²)_(q)OR⁹, and —(CR¹R²)_(q)R⁹ as provided in the definition of R⁴above. Such modifications may be done according to methods familiar tothose skilled in the art For instance, an amine moiety may be introducedby reductive amination of an aldehyde group. A compound of the formula 4can be obtained by treating a compound of the formula 3, wherein Z¹ isan activating group, such as bromo, iodo, —N₂, or —OTF (which is—OSO₂CF₃), with a coupling partner of the formula X¹—(CR¹R²)_(t)(C₆-C₁₀aryl) or X¹—(CR¹R²)_(t)(4-10 membered heterocyclic), wherein t, R¹ andR² are as defined above as provided in the definition of R⁴, the aryland heterocyclic groups of the foregoing groups are substituted with agroup that includes an aldehyde or acid moiety, and X¹ is —B(OH)₂ or—Sn(C₁-C₅ alkyl)₃. This reaction is generally done using palladium (0)or palladium (II) catalysts in a solvent such as DMF, THF(tetrahydrofuran), toluene, dioxanes, or a mixture of the foregoingsolvents, at 60-100° C. for about 8-24 hours. The compound of formula 2may be converted to the compound of formula 3 wherein Z is a substitutedphenoxy derivative by treating the starting compound with an appropriatemetal phenoxide, such as sodium phenolate, in a solvent, such as DMF orphenol, at a temperature ranging from about 0° C. to 100° C. for aperiod ranging from about 2 to 24 hours.

In the alternative, compounds of the formula 1 may be prepared accordingto the synthesis outlined in Scheme 2. In Scheme 2, a compound of theformula 1 may be obtained by treating a compound of formula 8, whereinZ² is as defined above, as described above regarding the conversion ofthe compound of formula 4 to a compound of formula 5. A compound of theformula 8 may be obtained by treating a compound of formula 7, whereinZ¹ is an activating group as defined above, as described above regardingthe conversion of the compound of formula 3 to a compound of formula 4.A compound of formula 7 may be obtained from a compound of formula 2 byreaction with an amine of the formula 6, HNR¹R³, wherein R¹ and R³ areas defined above, in a anhydrous solvent, in particular a solventselected from DMF, DME, DCE, t-butanol, and phenol, or a mixture of theforegoing solvents, a temperature within the range of about 50-150° C.for a period ranging from about 1 to 48 hours.

The starting compound of formula 2 may be prepared as illustrated inScheme 3. In Scheme 3, the compound of formula 11 wherein X is NH may beprepared from a compound of formula 9, wherein A and Z¹ are as definedabove and Z³ is OH, according to one or more procedures described in WO95/19774, referred to above, and a compound of formula 11 wherein X isCH may be prepared from a compound of formula 10, wherein A and Z¹ areas defined above, according to procedures described in WO 95/19774,referred to above. The compound of formula 11 may be converted to thecompound of formula 2 by treating the starting compound with achlorinating reagent, such as POCl₃ or ClC(O)C(O)Cl/DMF in a halogenatedsolvent at a temperature ranging from about 60° C. to 150° C. for aperiod ranging from about 2 to 24 hours.

The compounds of the present invention may have asymmetric carbon atoms.Diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, for example, bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixtures into a diastereomricmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomeric mixtures andpure enantiomers are considered as part of the invention.

The compounds of formulas 1 that are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate the compound of formula 1 from the reaction mixture asa pharmaceutically unacceptable salt and then simply convert the latterback to the free base compound by treatment with an alkaline reagent andsubsequently convert the latter free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent, such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is readily obtained. The desired acidsalt can also be precipitated from a solution of the free base in anorganic solvent by adding to the solution an appropriate mineral ororganic acid.

Those compounds of formula 1 that are acidic in nature are capable offorming base salts with various pharmacologically acceptable cations.Examples of such salts include the alkali metal or alkaline-earth metalsalts and particularly, the sodium and potassium salts. These salts areall prepared by conventional techniques. The chemical bases which areused as reagents to prepare the pharmaceutically acceptable base saltsof this invention are those which form non-toxic base salts with theacidic compounds of formula 1. Such non-toxic base salts include thosederived from such pharmacologically acceptable cations as sodium,potassium calcium and magnesium, etc. These salts can easily be preparedby treating the corresponding acidic compounds with an aqueous solutioncontaining the desired pharmacologically acceptable cations, and thenevaporating the resulting solution to dryness, preferably under reducedpressure. Alternatively, they may also be prepared by mixing loweralkanolic solutions of the acidic compounds and the desired alkali metalalkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensurecompleteness of reaction and maximum yields of the desired finalproduct.

The compounds of the present invention are potent inhibitors of the erbBfamily of oncogenic and protooncogenic protein tyrosine kinases such asepidermal growth factor receptor (EGFR), erbB2, HER3, or HER4 and thusare all adapted to therapeutic use as antiproliferative agents (e.g.,anticancer) in mammals, particularly in humans. In particular, thecompounds of the present invention are useful in the prevention andtreatment of a variety of human hyperproliferative disorders such asmalignant and benign tumors of the liver, kidney, bladder, breast,gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval,thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and neck, andother hyperplastic conditions such as benign hyperplasia of the skin(e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH). Itis, in addition, expected that a compound of the present invention maypossess activity against a range of leukemias and lymphoid malignancies.

The compounds of the present invention may also be useful in thetreatment of additional disorders in which aberrant expressionligand/receptor interactions or activation or signalling events relatedto various protein tyrosine kinases, are involved. Such disorders mayinclude those of neuronal, glial, astrocytal, hypothalamic, and otherglandular, macrophagal, epithelial, stromal, and blastocoelic nature inwhich aberrant function, expression, activation or signalling of theerbB tyrosine kinases are involved. In addition, the compounds of thepresent invention may have therapeutic utility in inflammatory,angiogenic and immunologic disorders involving both identified and asyet unidentified tyrosine kinases that are inhibited by the compounds ofthe present invention.

The in vitro activity of the compounds of formula 1 may be determined bythe following procedure.

The c-erbB2 kinase assay is similar to that described previously inSchrang et. al. Anal. Biochem. 211, 1993, p233-239. Nunc MaxiSorp96-well plates are coated by incubation overnight at 37° C. with 100 mLper well of 0.25 mg/mL Poly (Glu, Tyr) 4:1 (PGT) (Sigma Chemical Co.,St. Louis, Mo.) in PBS (phosphate buffered saline). Excess PGT isremoved by aspiration, and the plate is washed three times with washbuffer (0.1% Tween 20 in PBS). The kinase reaction is performed in 50 mLof 50 mM HEPES (pH 7.5) containing 125 mM sodium chloride, 10 mMmagnesium chloride, 0.1 mM sodium orthovanadate, 1 mM ATP, 0.48 mg/mL(24 ng/well) c-erbB2 intracellular domain. The intracellular domain ofthe erbB2 tyrosine kinase (amino acids 674-1255) is expressed as a GSTfusion protein in Baculovirus and purified by binding to and elutionfrom glutathione coated beads. The compound in DMSO (dimethylsulfoxide)is added to give a final DMSO concentration of about 2.5%.Phosphorylation was initiated by addition of ATP (adenosinetriphosphate) and proceeded for 6 minutes at room temperature, withconstant shaking. The kinase reaction is terminated by aspiration of thereaction mixture and subsequent washing with wash buffer (see above).Phosphorylated PGT is measured by 25 minutes of incubation with 50 mLper well HRP-conjugated PY54 (Oncogene Science Inc. Uniondale, N.Y.)antiphosphotyrosine antibody, diluted to 0.2 mg/mL in blocking buffer(3% BSA and 0.05% Tween 20 in PBS). Antibody is removed by aspiration,and the plate is washed 4 times with wash buffer. The colorimetricsignal is developed by addition of TMB Microwell Peroxidase Substrate(Kirkegaard and Perry, Gaithersburg, Md.), 50 mL per well, and stoppedby the addition of 0.09 M sulfuric acid, 50 mL per well. Phosphotyrosineis estimated by measurement of absorbance at 450 nm. The signal forcontrols is typically 0.6-1.2 absorbance units, with essentially nobackground in wells without the PGT substrate and is proportional to thetime of incubation for 10 minutes. Inhibitors were identified byreduction of signal relative to wells without inhibitor and IC₅₀ valuescorresponding to the concentration of compound required for 50%inhibition are determined.

The activity of the compounds of formula 1, in vivo, can be determine bythe amount of inhibition of tumor growth by a test compound relative toa control. The tumor growth inhibitory effects of various compounds aremeasured according to the method of Corbett T. H., et al., “TumorInduction Relationships in Development of Transplantable Cancers of theColon in Mice for Chemotherapy Assays, with a Note on CarcinogenStructure”, Cancer Res., 35, 2434-2439 (1975) and Corbett T. H., et al.,“A Mouse Colon-tumor Model for Experimental Therapy”, Cancer Chemother.Rep. (Part 2)”, 5, 169-186 (1975), with slight modifications. Tumors areinduced in the left flank by subcutaneous (sc) injection of 1-5 millionlog phase cultured tumor cells (murine FRE-ErbB2 cells or human SK-OV3ovarian carcinoma cells) suspended in 0.1 ml RPMI 1640 medium. Aftersufficient time has elapsed for the tumors to become palpable (100-150mm3 in size/5-6 mm in diameter) the test animals (athymic female mice)are treated with test compound (formulated at a concentration of 10 to15 mg/ml in 5 Gelucire) by the intraperitoneal (ip) or oral (po) routeof administration once or twice daily for 7 to 10 consecutive days. Inorder to determine an anti-tumor effect, the tumor is measured inmillimeters with a Vernier caliper across two diameters and the tumorsize (mm3) is calculated using the formula: Tumor size(mm3)=(length×[width]2)/2, according to the methods of Geran, R. I., etal. “Protocols for Screening Chemical Agents and Natural ProductsAgainst Animal Tumors and Other Biological Systems”, Third Edition,Cancer Chemother. Rep., 3, 1-104 (1972). Results are expressed aspercent inhibition, according to the formula: Inhibition(%)=(TuW_(control)−TuW_(test))TuW_(control)×100%. The flank site oftumor implantation provides reproducible dose/response effects for avariety of chemotherapeutic agents, and the method of measurement (tumordiameter) is a reliable method for assessing tumor growth rates.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to about 7 g/day,preferably about 0.2 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

The active compound may be applied as a sole therapy or may involve oneor more other ant-tumour substances, for example those selected from,for example, mitotic inhibitors, for example vinblastine; alkylatingagents, for example cis-platin, carboplatin and cyclophosphamide;anti-metabolites, for example 5-fluorouracil, cytosine arabinoside andhydroxyurea, or, for example, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex™ (tamoxifen) or, for example anti-androgens such as Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefor,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples, “Ac”means acetyl, “Et” means ethyl, “Me” means methyl, and “Bu” means butyl.

Where HPLC chromatography is referred to in the preparations andexamples below, the general conditions used, unless otherwise indicated,are as follows. The column used is a ZORBAX™ RXC18 column (manufacturedby Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. Thesamples are run on a Hewlett Packard-1100 systemA gradient solventmethod is used-running 100 percent ammonium acetate/acetic acid buffer(0.2 M) to 100 percent acetonitrile over 10 minutes. The system thenproceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutesand then 100 percent buffer solution for 3 minutes. The flow rate overthis period is a constant 3 ml/minute.

METHOD A Synthesis of(3-{4-[4-(1-Cyclopropylmethyl-1H-indol-5-ylamino)-guinazolin6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol(18) 6-Iodo-4quinazolinone (12)

A solution of 2-amino-5-iodobenzoic acid (26.3 g, 100 mmol) andformamidine acetate (13.5 g, 130 mmol) in ethanol (400 mL) was refluxedfor 20 hours. After cooling to 0° C., the solid product was collected byfiltration. Further drying in vacuo provided 6-iodo4-quinazolinone 12(22.0 g, 81%) as a grey crystalline solid. 1H NMR (400 MHz; DMSO-d₆) δ:12.38 (br. s, 1H), 8.35 (d, 1H), 8.05-8.10 (m, 2H), 7.43 (dd, 1H). LRMS:272.9 (MH+).

6-iodo-4-chloroquinazoline (13)

To a stirred solution of DMF (N,N-dimethylformamide) (6.3 mL) in DCE(dichloroethane) (20 mL) cooled to 0° C. was added dropwise a solutionof oxalyl chloride (60 mL of a 2M solution in DCE). After addition wascomplete, the cooling bath was removed and 6-iodo-3H-quinazolinone 12(10 g, 36.8 mmol) was added as a solid. The resulting mixture was heatedto reflux under nitrogen for 3 hours. Upon cooling to room temperature,the reaction was quenched cautiously with H₂O. CH₂Cl₂ was added and thebilayer transferred to a separatory funnel. The aqueous layer wasextracted with CH₂Cl₂ (2×50 mL) and the combined organic layers dried(Na₂SO₄). The solvent was removed in vacuo to provide a yellow solidwhich was triturated with diethyl ether to remove any remainingimpurities. The resulting yellow solid obtained by filtration was shownto be pure by NMR. For compound 13: ¹HNMR (CDCl₃, 400 MHz): δ: 9.05 (s,1H), 8.65 (d, 1H), 8.21 (dd, 1H), 7.78 (d, 1H).

6-iodo-4-phenoxyquinazoline (14)

A suspension of NaH (washed free of mineral oil) in DMF (40 mL) wascooled to 0° C. and a solution of phenol (5.65 g, 60 mmol) in DMF (20mL) was added dropwise. Upon completion of addition,6-iodo-4-chloroquinazoline 13 (14.6 g, 50.3 mmol) was added as a solidin small portions. The cooling bath was moved and the reaction mixturewas stirred at room temperature for 2 hours. The mixture was thenquenched with water (200 mL), diluted with EtOAc (300 mL) andtransferred to a separatory funnel. The organic layer was washed withdilute aqueous NaOH, water and brine and dried over Na₂SO₄. Filtrationof the solids and removal of the solvent provided6-iodo4-phenoxyquinazoline 14 (17.2 g, 98%) as a yellow solid. ¹H NMR(400 MHz; CDCl₃): δ: 8.74 (d, 1H), 8.14 (s, 1H), 8.12 (dd, 1H), 7.71 (d,1H). 7.49 (dd, 2H), 7.32 (t, 1H), 7.22 (m, 2H).

4-(4-Phenoxy-quinazolin-6-yl)benzaldehyde (15)

To a solution of toluene (211 mL) in a 1.0 L round-bottom flask equippedwith a reflux condenser was added 1,4-bis(diphenyl)phosphino)-butane(1.22 g, 2.87 mmol) and bis(benzonitrile)dichloro-palladium (1.1 g, 2.87mmol). The resulting solution was stirred at room temperature for 30minutes followed by the addition of THF (tetrahydrofuran) (255 mL) andEtOH (115 mL). To the resulting mixture was added6-iodo-4-phenoxy-quinazoline 14 (5.0 g, 14.4 mmol),4-formylphenylboronic acid (4.3 g, 28.7 mmol) and aqueous 1M Na₂CO₃ (29mL). The mixture was heated at reflux under an atmosphere of N₂ for 18hours. The reaction mixture was filtered hot and the solvent removedunder reduced pressure. The residue was taken up in CHCl₃ and washedwith water, brine, and dried (MgSO₄). The solvent was removed underreduced pressure and the residue was purified using flash chromatography(silica gel, EtOAc/hexanes 4:6) to provide (4.42 g, 13.54 mmol)4-(4-phenoxy-quinazolin-6-yl)benzaldehyde 15 in 94% yield. ¹H NMR (CDCl₃) δ7.26 (m, 3H), 2.88 (m, 1H), 7.51 (M, 2H), 7.92 (d, 2H, J=8.4 Hz),8.02 (d, 2H, J=8 Hz), 8.11 (d, 1H, J=8.8 Hz), 8.20 (dd, 1H, J=2.4 and8.8 Hz), 8.63 (d, 1H, J=2.4 Hz), 8.79 (s, 1H); MS (Cl) m/e 326 (M⁺+1,100).

3-[4-(4-Phenoxy-quinazolin6-yl)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol(16)

To a solution of 1:1 CHCl₃ and MeOH in a round-bottom flask under N₂ wasadded (3-aza-bicyclo[3.1.0]hex6-yl)-methanol 17 (2.27 g, 19.7 mmol)which was allowed to stir at room temperature for fifteen minutes. Tothe amine solution was added 4-(4-phenoxyquinazolin-6yl)benzaldehyde 15(3.78 g, 11.6 mmol) followed by the dropwise addition of acetic aciduntil the pH was approximately 6. NaCNBH₃ was added to the reactionmixture which was then allowed to stir overnight at room temperatureunder an atmosphere of N₂. The solution was diluted with CHCl₃ andwashed 3× with aqueous NaHCO₃ until the pH was approximately 9. Theorganic layer was separated, dried (MgSO₄) and removed under reducedpressure to provide a yellow viscous oil. The residue was purified byflash chromatography (silica gel, EtOAc-5%MeOH/EtOAc) to provide (3.51g, 8.28 mmol) compound 16 as a white solid in 71% yield. For compound16: ¹H NMR (CDCl₃ ) δ8.75 (s, 1H), 8.54 (d, 1H J=2 Hz), 8.17 (dd, 1HJ=8.4 and 2.4 Hz), 8.05 (d, 1H, J=8.4 Hz), 7.66 (d, 2H, J=8 Hz), 7.48(m, 2H), 7.39 (m, 2H), 7.32 (m, 1H), 7.25 (m, 2H), 3.65 (s, 2H), 3.44(d, 2H, J=3.6 Hz), 3.02 (d, 2H, J=8.8 Hz), 2.38 (d, 2H, J=8.4 Hz), 1.62(m, 1H), 1.30 (s, 2H); MS (Cl) m/e 423 (M⁺+1, 100).

(3-{-4-[4-(1-Cyclopropylmethyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)methanol(18)

To a 3 mL Wheaton vial was, added{3-[4-(4-phenoxy-quinazolin-6-yl)-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol16 (100 mg, 0.24 mmol), 1-cyclopropylmethyl-1H-indol-5-ylamine 19 (48mg, 0.26 mmol), pyridinium hydrochloride (33 mg, 0.284 mmol), and phenol(155 mg, 1.652 mmol). The vial was capped and heated overnight at 110°C. The vial was cooled to room temperature and the residue taken up inCHCl₃ and washed with 15% aqueous NaOH, water, brine, and dried (MgSO₄).The solvent was removed and the residue purified by flash chromatography(silica gel, EtOAc:MeOH, 95:5) to provide compound 18 (88 mg, 0.159mmol) as a light brown solid in 67% yield. For compound 18: MS (Cl) m/e515 (M⁺+1, 100); HPLC, rt=4.83 min.

METHOD B Synthesis of8-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol(1-Benzenesulfonyl-1H-indol-5-yl)-(6-iodo-quinazolin4-yl)-amine (20)

6-iodo-4-chloroquinazoline 13 (2.38 g, 8.20 mmol) and5-amino-1-benzenesulfonylindole 21 (2.46 g, 9.00 mmol) were combined inDCE (20 mL) and t-butanol (20 mL). The resulting mixture was heated atreflux under nitrogen for 18 hours to form a bright yellow suspension.Upon cooling the solids were filtered and rinsed with CH₂Cl₂ and placedunder high vacuum to remove any excess solvent. The title compound (3.23g, 75%) was obtained as a yellow solid. For compound 20: ¹H NMR(DMSO-d₆; 400 MHz): δ: 10.05 (s, 2H,), 8.93 (s, 1H), 8.53 (s, 1H), 8.25(m, 1H,), 8.10 (m, 5H), 7.97 (m, 3H), 7.82 (m, 2H), 7.70 (m, 2H), 7.65(m, 2H), 6.88 (d, 1H, J=3.57 Hz).

4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-guinazolin-6-yl]-benzaldehyde(22)

To a solution of toluene (100 mL) in a 500 mL round-bottom flaskequipped with a reflux condenser was added1,4-bis(diphenyl)phosphino)-butane (4.25 mg, 0.997 mmol) andbis(benzonitrile)dichloro-palladium (385 g, 0.997 mmol). Nitrogen wasbubbled through the reaction mixture for 1 minute and the resultingsuspension was stirred at room temperature for 30 minutes. THF (125 mL)and EtOH (50 mL) were then added. To the resulting mixture was added(1-benzenesulfonyl-1H-indol-5-yl)-(6-iodo-quinazolin-4-yl)-amine 20 (3.5g, 6.6 mmol), 4-formylphenylboronic acid (1.99 g, 13.3 mmol) and 2M aqNa₂CO₃ (6.7 mL). The mixture was heated at reflux under an atmosphere ofN₂ for 15 hours. The solvent was removed under reduced pressure and theresidue was purified using flash chromatography (silica gel,EtOAc/hexanes 1:1) to provide 3.1 g of4-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzaldehyde22 in 92% yield. ¹H NMR (DMSO-d₆; 400 MHz): δ: 9.24 (s, 1H, NH), 8.84(s, 1H), 8.33 (dd, 1H, J=8.9 Hz and 1.7 Hz), 8.01 (m, 4H), 7.90 (m, 2H),7.70 (m, 2H), 7.60 (m, 3H), 6.92 (dd, 1H, J=3.7 Hz and 0.6 Hz); MS (Cl)m/e 505.1 (M⁺+1, 100).

8-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol(23)

To a solution of CHCl₃ (1.5 mL) and MeOH (3 mL) in a round-bottom flaskunder N₂ was added 8-aza-bicyclo[3.2.1]octan-3-ol 24 (70 mg, 0.495mmol). AcOH was added to adjust the pH to 5. To the amine solution wasadded4-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzaldehyde22 (100 mg, 0.198 mmol) and the resulting solution was stirred at roomtemperature for 3 hours. NaCNBH₃ was added to the reaction mixture whichwas then allowed to stir overnight at room temperature under anatmosphere of N₂. The solution was diluted with CH₂Cl₂ and poured into1N NaOH (10 mL). The aqueous layer was separated and extracted withanother 2×15 mL of CH₂Cl₂. The organic layers were dried (MgSO₄) and thesolvent was removed under reduced pressure to provide a yellow viscousoil. The residue was purified by flash chromatography (silica gel,CH₂Cl₂-10%MeOH/CH₂Cl₂) to provide 45 mg of compound 23 as a white solidin 36% yield. HPLC, rt=5.25 min; MS (Cl) m/e 616.2 (M⁺+1, 100).

The following examples were prepared following either method A or methodB as described above. In the Table, the term “min” refers to minutes.

Method of Example prepar- LRMS Number ation IUPAC name (MH+) HPLC 1 A{6-[4-(6-Amino-3-aza-bicyclo[3.1.0]hex-3- 587.2 7.99 minylmethyl)-phenyl]-quinazolin-4-yl}-(1-benzenesulfonyl-1H-indol-5-yl)-amine 2 A{6-[4-(6-Amino-3-aza-bicyclo[3.1.0]hex-3- 498.3 5.09 minylmethyl)-phenyl]-quinazolin-4-yl}-(4- benzyl-phenyl)-amine 3 A{6-[4-(6-Amino-3-aza-bicyclo[3.1.0]hex-3- 500.3 4.93 minylmethyl)-phenyl]-quinazolin-4-yl}-(4- phenoxy-phenyl)-amine 4 A(3-{4-[4-(4-Benzyl-phenylamino)- 513.2 5.44 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 5 A(3-{4-[4-(4-Phenoxy-phenylamino)- 515.4 5.27 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 6 A(3-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 602.3 5.17 minylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 7 B (6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-526.4 5.43 min ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine 8 B (6-{4-[(1-Aza-bicyclo[2.2.2]oct-3- 526.45.52 min ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-benzyl-phenyl)-amine 9 B (6-{4-[(1-Aza-bicyclo[2.2.2]oct-3- 613.4 (−)5.33 min ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(1-benzenesulfonyl-1H-indol-5-yl)-amine 10 B(6-{4-[(3-Aza-bicyclo[3.1.0]hex-6- 500.3 4.93 minylamino)-methyl]-phenyl}-quinazolin-4-yl)- (4-phenoxy-phenyl)-amine 11 B(6-{4-[(3-Aza-bicyclo[3.1.0]hex-6- 498.3 5.10 minylamino)-methyl]-phenyl}-quinazolin-4-yl)- (4-benzyl-phenyl)-amine 12 B3-{4-[4-(4-Benzyl-phenylamino)- 558.3 4.47 min/5.77quinazolin-6-yl]-benzylamino}-8-methyl-8- minaza-bicyclo[3.2.1]octan-6-ol diastereomer 13 B(6-{4-[(3-Aza-bicyclo[3.1.0]hex-6- 587.2 4.80 minylamino)-methyl]-phenyl}-quinazolin-4-yl)-(1-benzenesulfonyl-1H-indol-5-yl)-amine 14 A (4-Benzyl-phenyl)-{6-[4-(6-527.3 6.06 min methoxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}- amine 15 A{6-[4-(6-Methoxymethyl-3-aza- 529.4 5.86 minbicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-(4-phenoxy-phenyl)- amine 16 A(1-Benzenesulfonyl-1H-indol-5-yl)-{6-[4- 616.2 5.64 min(6-methoxymethyl-3-aza- bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-amine 17 B (3-{4-[4-(4-Phenoxy-phenylamino)- 543.3 5.93min quinazolin-6-yl]-benzylamino}- bicyclo[2.2.1]hept-2-yl)-methanol 18B (3-{4-(4-(4-Benzyl-phenylamino)- 541.3 6.15 minquinazolin-6-yl]-benzylamino}- bicyclo[2.2.1]hept-2-yl)-methanol 19 B(3-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 630.2 5.78 minylamino)-quinazolin-6-yl]-benzylamino}-bicyclo[2.2.1]hept-2-yl)-methanol 20 A(4-Benzyl-phenyl)-(6-{4-[(8-methyl-8-aza- 540.4 5.97 minbicyclo[3.2.1]oct-3-ylamino)-methyl]- phenyl}-quinazolin-4-yl)-amine 21A (6-{4-[(8-Methyl-8-aza-bicyclo[3.2.1]oct-3- 542.3 5.76 minylamino)-methyl]-phenyl}-quinazolin-4-yl)- (4-phenoxy-phenyl)-amine 22 A(1-Benzenesulfonyl-1H-indol-5-yl)-(6-{4- 629.2 5.60 min[(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4- yl)-amine 23 A(3-{4-[4-(4-[1,2,3]Thiadiazol-5-yl- 507.3 4.41 minphenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 24 A(3-{4-[4-(4-Cyclohexyl-phenylamino)- 505.4 6.11 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 25 B8-Methyl-3-{4-[4-(4-phenoxy- 558.3 5.64 minphenylamino)-quinazolin-6-yl]- benzylamino}-8-aza-bicyclo[3.2.1]octan-6-ol 26 B 3-{4-[4-(1-Benzyl-1H-indol-5-ylamino)- 595.3 5.44 minquinazolin-6-yl]-benzylamino}-8-methyl-8- aza-bicyclo[3.2.1]octan-6-ol27 B 3-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 645. 3 5.53 minylamino)-quinazolin-6-yl]-benzylamino}-8-methyl-8-aza-bicyclo[3.2.1]octan-6-ol 28 A(3-{4-[4-(4-p-Tolyloxy-phenylamino)- 529.4 5.63 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 29 A(3-{4-[4-(Biphenyl-4-ylamino)-quinazolin- 499.3 5.36 min6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6- yl)-methanol 30 A(3-{4-[4-(4-Ethyl-phenylamino)- 451.3 4.73 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 31 A4-{6-[4-(6-Hydroxymethyl-3-aza- 542.2 4.30 minbicyclo[3.1.0]hex-3-ylmethyl)-phenyl]- quinazolin-4-ylamino}-N-phenyl-benzamide 32 A N,N-Diethyl-3-{6-[4-(6-hydroxymethyl-3- 522.3 4.05 minaza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-ylamino}-benzamide 33 A [3-(4- {4-4[3-Methyl-4-(pyridin-2-544.3 4.41 min ylmethoxy)-phenylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]- methanol 34 A(3-{4-[4-(4-Benzyloxy-phenylamino)- 529.3 5.21 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 35 A[3-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol- 568.3 4.73 min5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol 36 B8-Methyl-3-(4-{4-[1-(propane-2-sulfonyl)- 611.2 5.10 min1H-indol-5-ylamino]-quinazolin-6-yl}-benzylamino)-8-aza-bicyclo[3.2.1]octan- 6-ol 37 A(3-{4-[4-(1-Benzenesulfonyl-2-methyl- 616.2 5.47 min1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)- methanol 38 A(3-{4-[4-(1-Benzyl-1H-indazol-5- 553.3 4.69 minylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 39 A(3-{4-[4-(1-Methanesulfonyl-1H-indol-5- 540.2 4.21 minylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 40 A(3-{4-[4-(1-Ethanesulfonyl-1H-indol-5- 554.2 4.47 minylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 41 B(1-Benzenesulfonyl-1H-indol-5-yl)-(6-{4- 588.2 5.61 min[(3-oxa-bicyclo[3.1.0]hex-6-ylamino)-methyl]-phenyl≡-quinazolin-4-yl)-amine 42 B8-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 616.2 5.25 minylamino)quinazolin-6-yl]-benzyl}-8-aza- bicyclo[3.2.1]octan-3-ol 43 B8-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol- 582.2 4.84/4.96 min5-ylamino]-quinazolin-6-yl}-benzyl)-8-aza- bicyclo[3.2.1]octan-3-ol 44 B8-{4-[4-(4-Phenoxy-phenylamino)- 529.3 5.35 minquinazolin-6-yl]-benzyl}-8-aza- bicyclo[3.2.1]octan-3-ol 45 B8-{4-[4-(1-Benzyl-1H-indol-5-ylamino)- 566.3 5.23 minquinazolin-6-yl]-benzyl}-8-aza- (+) bicyclo[3.2.1]octan-3-ol 46 A(3-{5-[4-(4-Phenoxy-phenylamino)- 516.2 5.04 minquinazolin-6-yl]-pyridin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 47 A(3-{5-[4-(1-Benzenesulfonyl-1H-indol-5- 603.2 4.98 minylamino)-quinazolin-6-yl]-pyridin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)- methanol 48 A(3-{5-[4-(1-Benzyl-1H-indazol-5- 554.2 4.48 minylamino)-quinazolin-6-yl]-pyridin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)- methanol 49 A(3-{4-[4-(6-Phenoxy-pyridin-3-ylamino)- 516.2 4.74 minquinazolin-6-yl]-benzyl}-3-aza- bicyclo[3.1.0]hex-6-yl)-methanol 50 A(3-{5-[4-(4-Benzyloxy-phenylamino)- 530.2 4.98 minquinazolin-6-yl]-pyridin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 51 A [3-(5-{4-[3-Methyl-4-(pyridin-2-545.2 4.15 min ylmethoxy)-phenylamino]-quinazolin-6-yl}-pyridin-2-ylmethyl)-3-aza- bicyclo[3.1.0]hex-6-yl]-methanol 52 A(3-{5-[4-(4-Benzyl-phenylamino)- 514.3 5.18 minquinazolin-6-yl]-pyridin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 53 A {3-[4-(4-Phenoxy-phenylamino)-452.3 7.95 min quinazolin-6ylmethyl]-3-aza-bicyclo[3.1.0]hex-6-yl}methanol 54 B(5-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 630.1 5.43 minylamino)-quinazolin-6-yl]-benzyl}-5-aza- spiro[2.5]oct-1-yl)-methanol 55B (5-{4-[4-(4-Phenoxy-phenylamino)- 543.2 5.59 minquinazolin-6-yl]-benzyl}-5-aza- spiro[2.5]oct-1-yl)-methanol 56 B(6-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 630.2 5.36 minylamino)-quinazolin-6-yl]-benzyl}-6-aza- spiro[2.5]oct-1-yl)-methanol 57B (6-{4-[4-(4-Phenoxy-phenylamino)- 543.2 5.53 minquinazolin-6-yl]-benzyl}-6- azaspiro[2.5]oct-1-yl)-methanol 58 B(5-{4-[4-(1-Benzenesulfonyl-1H-indol-5- 616.1 5.34 minylamino)-quinazolin-6-yl]-benzyl}-5-aza- spiro[2.4]hept-1-yl)-methanol59 B (5-{4-[4-(4-Phenoxy-phenylamino)- 529.4 5.50 minquinazolin-6-yl]-benzyl}-5-aza- (+) spiro[2.4]hept-1-yl)-methanol 60 B(5-{4-[4-(4-Phenoxy-phenylamino)- 543.2 5.91 minquinazolin-6-yl]-benzyl}-5-aza- spiro[2.5]oct-1-yl)-methanol

The following compounds (and their pharmaceutically acceptable salts andsolvates, and all stereoisomers including any endo and exo isomers)which are part of the present invention, may be prepared using themethods described above and/or methods familiar to those skilled in theart:

(3-{4-[4-(3-Fluoro-4-phenoxy-phenylamino)-quinazolin6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex6-yl)-methanol;

(3-{4-[4-(4-Phenoxy-3-trifluoromethyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

(3-{4-[4-(3-Chloro4-phenoxy-phenylamino)-quinazolin6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex4-yl)-methanol;

(5-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)-methanol;

8-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;

8-{4-[4-(1-Benzyl-1H-indol-5-ylamino)-quinazolin6-yl]-benzyl}-8-aza-bicyclo[3,2.1]octan-3-ol;

8-{4-[4-(3-Chloro4-phenoxy-phenylamino)-quinazolin6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;

8-{4-[4-(3-Methyl4-phenoxy-phenylamino)-quinazolin6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;

8-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin6-yl}-benzyl)-8-aza-bicyclo[3.2.1]octan-3-ol;

(3-{4-[4-(4-Benzyloxy-3-methyl-phenylamino)-quinazolin6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex6-yl)-methanol;

[3-(4-{4-[1-(4-Methyl-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex6-yl]-methanol;

[3-(4-{4-[1-(4-Methoxy-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex6-yl]-methanol;

[3-(4-{4-[1-(3-Methyl-benzyl)-1H-indazol-5-ylamino]-quinazolin6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex6-yl]-methanol;

[3-(4-{4-[1-(3-Methoxy-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex6-yl]-methanol;

[3-(4-{4-[1-(2-Fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol;

(3-{4-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

{6-[4-(6-Dimethylamino-3-aza-bicyclo[3.10]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-3-methoxy-4-phenoxy-phenyl)-amine;

{6-[4-(6-Dimethylamino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-(3-methyl4-phenoxy-phenyl)-amine;

(3-{3-[4-(3-Methyl4-phenoxy-phenylamino)-quinazolin-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

(3-{3-[4-(3-Methoxy4-phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;

{6-[3-(6-Dimethylamino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin4-yl}-(3-methoxy4-phenoxy-phenyl)-amine;

{6-[3-(6-Dimethylamino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin4-yl}-(3-methyl-4-phenoxy-phenyl)-amine;

{6-[3-(6-Amino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-(3-methoxy-4-phenoxy-phenyl)-amine;

(3-{4-[4-(3-Methyl4-o-tolyloxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.10.]hex6-yl)-methanol;

[3-(4-{4-[4-(2-Methoxy-phenoxy)-3-methyl-phenylamino]-quinazolin6-yl}benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol;and,

[3-(4-{4-[4-(2-Fluoro-phenoxy)-3-methyl-phenylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol.

What is claimed is:
 1. A compound of the formula 1

or a pharmaceutically acceptable salt or solvate thereof, wherein: X isN; A represents a fused 6-membered ring, the fused ring containing atotal of 3 double bonds inclusive of the bond in the pyrimidine ring towhich it is fused and wherein the carbon atoms of the A moiety areoptionally substituted by 1 to 3 R⁵ groups; each R¹ and R² isindependently H or C₁-C₆ alkyl; R³ is —(CR¹R²)_(m)-R⁸ wherein m is 0 or1; or R¹ and R³ are taken together to form a group of the formula

 wherein said group is optionally substituted with 1 to 3 R⁵ groups; R⁴is —(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5, wherein said R⁴groups are substituted with 1 to 3 groups independently selected from—(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl),—(CR¹R²)_(q)O(CR¹R²)_(r)R⁹, and —(CR¹R²)_(q)R⁹ wherein q and r are eachindependently an integer from 0 to 5, and wherein the heterocyclic, aryland alkyl moieties of the foregoing groups are optionally substitutedwith 1 to 3 R¹⁰ groups; each R⁵ is independently selected from halo,hydroxy, —NR¹R², C₁-C₆ alkyl, trifluoromethyl, C₁-C₆ alkoxy, andtrifluoromethoxy; each R⁶ and R⁷ is independently selected from H, C₁-C₆alkyl, —(CR¹R²)_(t)(C₆-C₁₀ aryl), and —(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbonatoms of the heterocyclic group are optionally substituted with an oxo(═O) moiety, and the alkyl, aryl and heterocyclic moieties of theforegoing R⁶ and R⁷ groups are optionally substituted with 1 to 3substituents independently selected from halo, cyano, nitro, —NR¹R²,trifluoromethyl, trifluoromethoxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, hydroxy, and C₁-C₆ alkoxy; each R⁸ is independently selectedfrom —(CR¹R²)_(t)(C₆-C₁ aryl) and —(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbonatoms of the heterocyclic group are optionally substituted with an oxo(═O) moiety, and each of the foregoing R⁸ groups is optionallysubstituted with 1 to 5 R¹⁰ groups; R⁹ is a fused or bridged bicyclicring or a spirocyclic ring, wherein said ring contains from 5 to 12carbon atoms in which up to 2 carbon atoms are optionally replaced witha hetero moiety selected from O, S(O)_(j) wherein j is an integer from 0to 2, and —NR¹¹—, provided that two O atoms, two S(O)_(j) moieties, an Oatom and a S(O)_(j) moiety, an N atom and an S atom, or an N atom and anO atom are not attached directly to each other, and wherein said ring issaturated or partially unsaturated with up to two carbon-carbon doublebonds, and the carbon atoms of said ring are optionally substituted with1 to 4 R¹⁰ groups; or where R⁹ is as —NR¹R⁹ then R⁹ optionally can betaken together with R¹ and the nitrogen to which R¹ and R⁹ are attachedto form a fused or bridged bicyclic ring or a spirocyclic ring, whereinsaid ring is saturated and contains from 5 to 12 carbon atoms in whichup to 2 carbon atoms are optionally replaced with a hetero moietyselected from O, S(O)_(j) wherein j is an integer from 0 to 2, and—NR¹—, provided that two O atoms, two S(O)_(j) moieties, or an O atomand a S(O)_(j) moiety are not attached directly to each other, andwherein the carbon atoms of said rings are optionally substituted with 1to 4 R¹⁰ groups; each R¹⁰ is independently selected from halo, cyano,nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C₁-C₆ alkoxy,C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)R⁵, —C(O)OR⁶, —OC(O)R⁶,—NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, —SO₂NR⁶R⁷, —S(O)_(j)(C₁-C₆alkyl) wherein j is an integer from 0 to 2, —(CR¹R²)_(t)(C₆-C₁₀ aryl),—(CR¹R²)_(t)(4-10 membered heterocyclic),—(CR¹R²)_(q)C(O)(CR¹R²)_(t)(C₆-C₁₀ aryl),—(CR¹R²)_(q)C(O)(CR¹R²)_(t)(4-10 membered heterocyclic),—(CR¹R²)_(t)O(CR¹R²)_(q)(C₆-C₁₀ aryl), —(CR¹R²)_(t)O(CR¹R²)_(q)(4-10membered heterocyclic), —(CR¹R²)_(q)SO₂(CR¹R²)_(t)(C₆-C₁₀ aryl), and—(CR¹R²)_(q)SO₂(CR¹R²)_(t)(4-10 membered heterocyclic), wherein q and tare each independently an integer from 0 to 5, 1 or 2 ring carbon atomsof the heterocyclic moieties of the foregoing R¹⁰ groups are optionallysubstituted with an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl,aryl and heterocyclic moieties of the foregoing R¹⁰ groups areoptionally substituted with 1 to 3 substituents independently selectedfrom halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR⁶,—C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —(CR¹R²)_(t)(C₆-C₁₀ aryl),and —(CR¹R²)_(t)(4-10 membered heterocyclic), wherein t is an integerfrom 0 to 5; R¹¹ is H, C₁-C₆ alkyl, —C(O)R⁶ or —SO₂R⁶; and wherein anyof the above-mentioned substituents comprising a CH₃ (methyl), CH₂(methylene), or CH (methine) group which is not attached to a halogeno,SO or SO₂ group or to a N, O or S atom optionally bears on said group asubstituent selected from hydroxy, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy and—NR¹R².
 2. A compound according to claim 1 wherein R⁴ is—(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10 membered heterocyclic),wherein t is an integer from 0 to 5, wherein said R⁴ groups aresubstituted with 1 to 3 groups independently selected from—(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl),—(CR¹R²)_(q)O(CR¹R²)_(r)R⁹, and —(CR¹R²)_(q)R⁹ wherein q and r are eachindependently an integer from 0 to 3, and wherein the heterocyclic, aryland alkyl moieties of the foregoing groups are optionally substitutedwith 1 to 3 R¹⁰ groups.
 3. A compound according to claim 1 wherein R³ is—(CR¹R²)_(m)—R⁸ wherein m is 0 or 1 and R⁸ is selected from —(CR^(R)²)_(t)(phenyl), —(CR¹R²)_(t)(pyridyl), —(CR¹R²)_(t)(pyrimidinyl),—(CR¹R²)_(t)(indolyl), —(CR¹R²)_(t)(indazolyl) and—(CR¹R²)_(t)(benzimidazolyl), wherein t is an integer from 0 to 5, andeach of the foregoing R⁸ groups is optionally substituted with 1 to 5R¹⁰ groups.
 4. A compound according to claim 1 selected from the groupconsisting of:{6-[4-(6-Amino-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-(4-phenoxy-phenyl)-amine;(3-{4-[4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol:(3-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(3-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine;(6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-benzyl-phenyl)-amine;6-{4-[(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(1-benzenesulfonyl-1H-indol-5-yl)-amine;6-{4-[(3-Aza-bicyclo[3.1.0]hex-6-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-(4-phenoxy-phenoxy)-amine;3-{4-[4-(4-Benzyl-phenylamino)-quinazolin-6-yl]-benzylamino}8-methyl-8-aza-bicyclo[3.2.1]octan6-ol;(4-Benzyl-phenyl)-{6-[4-(6-methoxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin4-yl}amine{6-[4-(6-Methoxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-yl}-(4-phenoxy-phenyl)-amine;(3-{4-[4-(4-[1,2,3]Thiadiazol-5-yl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(3-{4-[4-(4-Cyclohexyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(3-{4-[4-(4-p-Tosyloxy-phenylamino)-quinazolin6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex6-yl)-methanol;(3-{4-[4-(Biphenyl-4-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex6-yl)-methanol;(3-{4-[4-(4-Ethyl-phenylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;4-{6-[4-(6-Hydroxymethyl-3-aza-bicyclo[3.1.0]hex-3-ylmethyl)-phenyl]-quinazolin-4-ylamino}-N-phenyl-benzamide;[3-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-yl}-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-methanol;(3-{4-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(1-Benzenesulfonyl-1H-indol-5-yl)-(6-{4-[(3-oxa-bicyclo[3.1.0]hex-6-ylamino)-methyl]-phenyl}-quinazolin-4-yl)-amine;8-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;8-(4-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-yl}-benzyl)-8-aza-bicyclo[3.2.1]octan-3-ol;8-{4-[4-(4-Phenoxy-phenylamino)-quinazolin6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;8-{4-[4-(1-Benzyl-1H-indol-5-ylamino)-quinazolin6-yl]-benzyl}-8-aza-bicyclo[3.2.1]octan-3-ol;(3-{4-[4-(6-Phenoxy-pyridin-3-ylamino)-quinazolin-6-yl]-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;(3-{5-[4-(4-Benzyl-phenylamino)-quinazolin6-yl]-pyridin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;{3-[4-(4-Phenoxy-phenylamino)-quinazolin-6ylmethyl]-3-aza-bicyclo[3.1.0]hex-6-yl}methanol;(5-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl)}-5-aza-spiro[2.5]oct-1-yl)-methanol;(5-{4-[4-(4-Phenoxy-phenylamino)-quinazolin-6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)-methanol;(6-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzyl}-aza-spiro[2.5]oct-1-yl)-methanol;(6-{4-[4-(4-Phenoxy-phenylamino)-quinazolin6-yl]-benzyl}-6aza-spiro[2.5]oct-1-yl)-methanol;(5-{4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin6-yl]-benzyl}-5-aza-spiro[2.4]hept-1-yl)-methanol;(5-{4-[4-(4-Phenoxy-phenylamino)-quinazolin6-yl]-benzyl}-5-aza-spiro[2.4]hept-1-yl)-methanol;(5-{4-[4-(4-Phenoxy-phenylamino)-quinazolin6-yl]-benzyl}-5-aza-spiro[2.5]oct-1-yl)-methanol;and the pharmaceutically acceptable salts and solvates of the foregoingcompounds.
 5. A method of preparing a compound of claim 1 whichcomprises either (a) reacting a compound of the formula 5 with acompound of the formula 6

wherein Z is a leaving group and A, X, R¹, R³, and R⁴ are as defined inclaim 1, or (b) reacting a compound of the formula 2 with a compound ofthe formula 6

wherein X, A, R¹, and R³ are as defined in claim 1 and Z¹ is anactivating group, to provide an intermediate of the formula 7

wherein Z¹, X, A, R¹, and R³ are as defined in claim 1, and treating thecompound of formula 7 with a coupling partner of the formulaX¹—(CR¹R²)_(t)(C₆-C₁₀ aryl) or X¹—(CR¹R²)_(t)(4-10 memberedheterocyclic), wherein t, R¹ and R² are as defined in claim 1 asprovided in the definition of R⁴, the aryl and heterocyclic groups ofthe foregoing groups are substituted with a group that includes analdehyde or acid moiety, and X¹ is —B(OH)₂ or —Sn(C₁-C₅ alkyl)₃, toprovide a compound of formula 8

wherein X, A, R¹, and R³ are as defined above, and Z² is—(CR¹R²)_(t)(C₆-C₁₀ aryl) or —(CR¹R²)_(t)(4-10 membered heterocyclic),wherein t, R¹ and R² are as defined in claim 1, and the aryl andheterocyclic groups of the foregoing Z² groups are substituted with agroup that includes an aldehyde or acid moiety, and modifying saidaldehyde or acid moiety to introduce a group selected from—(CR¹R²)_(q)NR¹R⁹, —(CR¹R²)_(q)NR⁹(C₁-C₆ alkanoyl), —(CR¹R²)_(q)OR⁹ and—(CR¹R²)_(q)R⁹ wherein R¹, R², R⁹ and q are as defined in the definitionof R⁴ in claim
 1. 6. A pharmaceutical composition for the treatment ofskin cancer in a mammal comprising an amount of a compound of claim 1that is effective in treating skin cancer, and a pharmaceuticallyacceptable carrier.
 7. A method for the treatment of skin cancer in amammal which comprises administering to said mammal an amount of acompound of claim 1 that is effective in treating skin cancer incombination with an anti-tumor agent selected from the group consistingof mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens. 8.A method for the treatment of skin cancer in a mammal comprisingadministering to said mammal an amount of a compound of claim 1 that iseffective in treating skin cancer.